ArticleNature communications2026
Design, synthesis and structural mechanism of action of TRPV1 agonist MSP20 with long-lasting analgesic effect.
Article in Nature communications, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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23 authors.
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Abstract
Transient receptor potential vanilloid type-1 (TRPV1) channel is a polymodal receptor involved in pain perception and neuronal signalling that represents a promising target for the development of analgesics and neuroprotective agents. In this study we implement a combination of computational techniques and targeted design of chemical libraries to discover benzothiophene-substituted TRPV1 agonists with high affinity and efficacy toward TRPV1. In vitro functional experiments show that prolonged or repeated exposure to these compounds induce calcium-dependent desensitization of TRPV1, making it insensitive to noxious stimuli. We solve a cryo-electron microscopy (cryo-EM) structure of human TRPV1 (hTRPV1) in complex with the most promising benzothiophene-substituted agonist MSP20. The structure reveals molecular details of MSP20 binding to the vanilloid site and a desensitized conformation of hTRPV1, characterized by the closed ion channel pore, α-helical C-terminus and distinct behaviour of annular lipids. Our in vivo experiments demonstrate that MSP20 exhibits robust and long-lasting antinociceptive activity with ex-vivo neuroprotective effects, supporting the perspective of benzothiophene-substituted vanilloids as future analgesics.
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